Collagen crosslinking (by applying riboflavin and UV-A light radiation) has been used in the past years in ophthalmology for the treatment of patients with maceration diseases of the cornea (the translucent part of the adventitia in the front part of the eye) (Wollensak et al., American Journal of Ophthalmology 2003, 135:620-627). The application of substances and light is significantly easier in the front part of the eye, since this part can be reached directly without surgical procedures.
Collagen crosslinking of the sclera for the treatment of progressive myopia (scleral crosslinking) is new and has so far only been tested in animal experiments (Iseli et al., Journal of Refractive Surgery 2008, 24:752-755; Wollensak et al., Acta Ophthalmologica Scandinavica 2005, 83: 477-482).
At this point in time there is no system for substance application or radiation for an extensive treatment of the outer part of the eye (especially the posterior and equatorial areas of the sclera) for the treatment of pathological deformation of the sclera. On the one hand, this therapeutic approach for the treatment of progressive myopia (scleral crosslinking through riboflavin and blue-light therapy) is completely new, and on the other hand, there are no therapeutic approaches for other diseases that would have required a substance application-/radiation system in ophthalmology.
In the inventor's experimental research, the photosensitive substance (riboflavin) was dripped into the Tenon's space and radiation ensued with a light application system (Bluephase 16i, Ivoclar Vivadent GmbH, Ellwangen-Jagst, Germany) which was designed for use in dentistry. For the use in our field, the inventors made several modifications (such as certain attachments to regulate the amount of light-energy). An extensive and homogenous radiation especially of the rear areas of the sclera is not possible with this auxiliary system. Substances have to be applied separately and alternating with radiation and will spread unevenly throughout the entire Tenon's space. This system is completely unsuitable for use in human eye surgery, since, inter alia, it cannot factor in the anatomy (size and shape of the human eye, muscle and nerve endings, vascular anatomy, etc).
Known instruments for substance application are designed for the localized application on the fibrous connective tissue directly on the sclera (episclera, sub-Tenon's space). Known patents describe a substance application under the episclera/sub-Tenon's space (WO 01/28473 A1, US 2010/0114039 A, WO 03/009784 A1) or they are meant for the localized application on the conjunctiva (WO 2010/105130 A2). These applications are aimed at small-scale, rather selective treatment of the retina; i.e. the sub-scleral tissue in the innermost part of the eye (see also FIG. 1). The substance thus has to first penetrate the outer tissue of the eye such as sclera and choroidea to reach its target location, the retina. The known systems only use the exterior application to the sclera to avoid the surgical application directly into the eye on the surface of the retina. These methods still bear the risk of post-surgical inflammation and injuries of the adventitia of the eye and are also not designed for the treatment of scleral tissue. The therapeutic aim of these treatment methods is thus a completely different one. The substance application and radiation system (SAIS-Spot) according to the present invention is applied directly to the site of the sclera that is to be treated in the Tenon's space (the space between the eye and the orbital cavity; see FIG. 1). The presently claimed system is positioned exactly where the treatment site is; i.e. the outer scleral tissue. Our approach does not involve any increased risk of complications during and after surgery vis-à-vis established surgical methods.
Applicators that have been described so far are used to form or release depots for medicine (WO 01/28473 A1, US 2010/0114039 A) and are not designed to release medicine/agents during surgical treatment and to then be removed again after surgery.
WO 03/009784 A1 suggests to implant a medication depot permanently into the sub-Tenon's space, it will thus not be removed at the end of surgery. As has already been mentioned, all of these applicators have the retina as primary target tissue. The present application is directed to the treatment of the sclera. None of the applicators is capable of covering the sclera sufficiently for treatment. All existing applicators have to be understood as local small-scale applicators, they affect a completely different target tissue and have different treatment approaches for different diseases. Additionally, all applicators cannot really regulate the substances application/delivery. Furthermore, none of these applicators can ensure an undesired diffusion of the substances and that adjacent tissues will not be affected by the treatment.
WO 2012/058382 A2 describes a device for delivering an active agent to target tissue at a site that includes a bodily fluid. The device includes a body having a first exterior surface including a first section having a local, discrete recessed area formed in the body for holding the active agent. The body includes a surface flow feature in the form of a canal that is formed in the body and is recessed relative to the exterior surface. The surface flow feature interfaces with the first section and the local recessed area and is configured so as to guide or modify flow of the bodily fluid relative to the body such that fluid communication is provided between the bodily fluid and the local recessed area. The local recessed area is recessed relative to at least a portion of the canal. The device can also be in the form of a device that has an erodible member that releases the active agent over a prescribed period of time.
WO 2006/058189 A2 provides a medical device having a thermistor for temperature measurement, irrigation/aspiration ports for fluid exchange and application of therapeutic modalities, a pressure manometer for pressure measurement, and an external system for control of temperature, pressure, and flow rate. When applied to the eye and orbit, this device can be used in hypothermia or hyperthermia applications, the control of intraocular pressure (IOP), and the application of treatment modalities. Methods of using the device in treating patients suffering from central retinal artery occlusion, anterior optic nerve disease, pathology of the choroid and retina including the macula, inflammation of the eye including the vitreous and anterior segment, glaucoma, inflammation and/or infections of the anterior and/or posterior segment of the eye, treatment before/during/after surgery of the eye, and the application of treatment modalities through a semipermeable membrane are described.
In WO 2008/011125 A2, devices, systems and techniques for delivering drugs to an ocular tissue are described. In at least some embodiments, a terminal component (e.g., a needle or open end of a catheter) is implanted in an ocular tissue and used to deliver one or more drugs. The delivered drugs may come from a source which is also implanted, or may be introduced from an external source (e.g., via a port). Both solid and liquid drug formulations can be used. Ocular implants can alternatively include a thin film coating that releases a drug into an ocular tissue.
U.S. Pat. No. 5,725,493 A discloses an intravitreal medicine delivery device and method including an implant device through which a wide variety of beneficial medicines including drugs or other pharmacological agents can be introduced into the vitreous cavity over an extended period of time with only a single initial surgery to implant the device. The device and method minimize the surgical incision needed for implantation and avoid future or repeated invasive surgery or procedures. Additional amounts of the initial medicine can readily be introduced or the medication can be varied or changed, as required. Furthermore, the device and method allow the dosage delivered to the vitreous cavity to be controlled, and the device is constructed so as to filter medicines delivered to the cavity and also avoids damage to or interference with other parts of the eye during implantation or during use.
WO 02/074196 A1 describes ocular implant devices for the delivery of a therapeutic agent to an eye in a controlled and sustained manner. Dual mode and single mode drug delivery devices are illustrated and described. Implants suitable for subconjunctival placement are described. Implants suitable for intravitreal placement also are described. The invention also includes fabrication and implementation techniques associated with the unique ocular implant devices that are presented herein.
US 2012/0209051 describes delivery systems and methods for delivering riboflavin (R/F) and UVA irradiation to the sclera. The R/F is delivered and then activated with UVA irradiation through the use of LEDs or optical fibers and separate cooling substance channels for the LEDs, thereby causing cross-linking of the collagen tissue. Delivery systems include implantable structures which provide surfaces that conform to the sclera. The delivery systems include various types of structures for delivery of R/F onto the sclera surface. Additionally, the delivery systems include UVA sources which provide irradiation of R/F in sclera collagen tissue.
None of the existing prior art describes the introduction of separate systems into the same application system (e.g. agent/substance and electromagnetic waves, or the application of different separate agents) which can be essential for the method of collagen crosslinking. None of the prior art allows for the control of a finely tuned localized medication release or a simultaneous dosing of the radiation. Suction systems for superfluous substances/agents are also not provided for in these applicators.
So far, there is no application system which is suitable for use on the sclera with the new treatment approach according to the invention. Existing substance applicators are designed for localized application of substances in cases when the tissue targeted for treatment is not the sclera but the underlying tissue (mostly the retina in the inner part of the eye). The presently claimed applicator can apply substances, electromagnetic waves, such as light, or heat extensively and in a controlled manner to all parts of the sclera, which has not been possible so far.
A shortcoming in the system that has so far been used in animal experiments is the size of the radiation unit in restricted spaces, which leads to severe or dangerous manipulation of the eye. An extensive and homogenous radiation also of the back parts of the sclera is not possible with this auxiliary system. Furthermore, the radiation system only radiates in certain predetermined time intervals. It is not possible to freely control the radiation energy levels. Since the only light power settings in the radiator employed by us were 50% or 100%, auxiliary plastic attachments had to be developed which enabled the use of graduated light power levels. Substances could only be applied by dripping them onto the tissue which leads to an inhomogeneous distribution of the substance. Thus, the substance also reaches tissue areas that are not supposed to be treated. Moreover, substance applicators and parallel systems (e.g. light) cannot be used simultaneously. There are no specially formed suction systems. So far, it is also not possible to extensively treat the middle and rear part of the eye/sclera.
The invention resolves disadvantages of the auxiliary system from the animal experiments and of other systems and treatment approaches respectively. Such disadvantages are:                anatomically unsuitable for extensive/comprehensive treatment of the sclera in view of the anatomy of the treated eye        the locally or temporally parallel application of different substances is not possible        a temporal and local combination of substance application and electromagnetic radiation (e.g. light) and/or electricity (monopolar and bipolar coagulation) is not possible; the necessary alternation between the application of substances and light leads to a considerable increase in the duration of surgery/treatment        protein coagulation or the application of heat is not possible        since substance and light applicators have to be attached and detached periodically alternating, the treatment becomes inhomogeneous because the surgeon has to constantly rearrange everything; moreover, the attaching and detaching bears an increased risk of damaging the surrounding tissue        there is no return/suction system for superfluous substances, tissue not to be treated is always affected/co-treated        there is no protection for radiation sensitive substances from the radiation until the radiation has arrived at the application-/treatment site (no shielding of the substance feeding exists)        known application systems cannot be introduced under visual control (video system)        known systems cannot supply a high light quantity to the sclera        known systems cannot detect the contact between the applicator and the sclera        
So far, there is no application system that is suitable for use on the sclera or the treatment approach according to the invention. The therapeutic approach for the treatment of progressive myopia or pathological changes due to sclera maceration is completely new. Therefore, there is no surgical equipment that meets the requirements of this method of treatment or this surgical procedure. Individual technical methods for substance application or for the radiation of areas/tissue are always streamlined for their specific uses and do not fulfil the requirements of our therapeutic approach. There is a need for an extensive system for the homogeneous substance application and/or radiation that takes the exact anatomic structure of the eye into account and meets all the technical requirements of the treatment or the surgical procedure.
The disadvantages and shortcomings of the substance application and the radiation unit used in the animal experiments would also be eliminated by the new application system (SAIS-Spot).